Pharmacokinetic Interaction between Darunavir/ritonavir and Efavirenz in Healthy HIV Negative Volunteers

In June 2007, the U.S. Food and Drug Administration (FDA) approved the novel protease inhibitor (PI) darunavir (Prezista; TMC114) for use by heavily treatment-experienced HIV patients in combination with other antiretroviral agents.

As with other PIs, darunavir may interact with other medications used by people with HIV, because the drug is metabolized by the CYP3A4 enzyme in the liver.

In the current open-label study, published in Antiviral Therapy, researchers at Tibotec Therapeutics in Yardley, PA, investigated the pharmacokinetic interaction between darunavir, administered with low-dose ritonavir, and efavirenz (Sustiva) in healthy, HIV-negative volunteers.

Volunteers received darunavir/ritonavir 300/100 mg twice daily for 6 days, and once on day 7 (session 1). After a 7-day washout period, volunteers received efavirenz 600 mg once daily for 18 days (session 2), with co-administration of darunavir/ritonavir 300/100 mg twice daily from day 11 through day 16 and darunavir/ritonavir once on day 17.

Results

• When co-administered with darunavir/ritonavir, plasma concentrations of efavirenz were slightly increased.

• In the presence of darunavir/ritonavir, efavirenz minimum (Cmin) and maximum (Cmax) plasma concentrations increased by 15%-17%.

• Efavirenz area under the curve (AUC24h) increased by 21%.

• Darunavir/ritonavir and efavirenz co-administration resulted in darunavir Cmin, Cmax and AUC12h decreases of 31%, 15%, and 13%, respectively.

• No serious adverse events (AEs) or AEs leading to withdrawal were reported in this trial.

• Overall, darunavir/ritonavir and efavirenz co-administration was well tolerated.

Conclusion

The study authors concluded, "The clinical significance of the changes in AUC and Cmin seen with [darunavir/ritonavir] and efavirenz coadministration has not been established.

Further, they noted, "This combination should be used with caution. Similar findings are expected with the approved darunavir/ritonavir 600/100 mg twice daily dose."

08/28/07

Reference
V J Sekar, M De Pauw, K Mariën, and others. Pharmacokinetic interaction between TMC114/r and efavirenz in healthy volunteers. Antiviral Therapy 12(4): 509-514. 2007.